Diseases associated with abnormalities in synucleins are often referred to as the synucleinopathies. Synucleinopathies include the neurodegenerative conditions, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).
Synucleins are a family of small proteins, about 14 kDa that are expressed at high levels in nervous tissues. Three members of the family are α-, β-, and γ-synucleins. α-Synuclein is expressed mainly in brain tissues and is primarily located at the presynaptic terminal of neurons. α-Synuclein normally exists as a soluble monomeric protein but can adopt several different folded confirmations depending on its environment. Monomeric α-synuclein can also aggregate into oligomers and into higher molecular weight insoluble fibrils. α-Synuclein aggregation proceeds from monomeric α-synuclein through to the formation of soluble oligomers (early aggregates), which then converts into higher molecule weight ordered fibrils (late aggregates).
In synucleinopathies it has been shown that soluble α-synuclein oligomers in brain homogenates of PD and DLB are elevated compared to normal brains. While neuropathological studies of PD have revealed the presence of cytoplasmic inclusions found in the degenerating dopaminergic neurons of the substantia nigra and other cortical and subcortical neurons. These lesions in the brain are known as Lewy bodies and Lewy neurites and have also been shown to constitute the main pathological features in the brain of DLB patients. These neuropathologic lesions often characterise the end stage of PD and DLB have largely been found to be composed of fibrillar α-synuclein deposits. Additional studies have shown that α-synuclein is also associated with pathological lesions in other neurodegenerative diseases sometimes involving non-neuronal cells, such as the cytoplasmic inclusions found in MSA.
Chinese medicinal compositions derived from medicinal herbs and plants have been used in the treatment of a wide range of diseases for many hundreds of years. Traditional Chinese medicine has been used as remedies for various disorders including dementia and other neurodegenerative disorders. Effort has been put into determining the pharmacological basis behind traditional Chinese medicinal compositions.
Ginseng is one Chinese medicinal composition that has been studied. The pharmacological properties of ginseng are mainly attributed to its biologically active ingredients, the ginsenosides. The ginsenosides can be extracted from many parts of the ginseng plant including the root, leaves and ginseng berries. Ginsenosides are derivatives of triterpenoid dammarane with a four-ring, steroidal structure bearing sugar moieties and an aliphatic side chain.
Another Chinese medicinal composition is danshen. Pharmacological properties of danshen have been attributed to salvianolic acid B and its anti-oxidative ability. A further Chinese medicinal composition is the Japanese raisin tree. The pharmacological properties of the Japanese raisin tree have been attributed to dihydromyricetin, a flavonoid, and the compound has been used as a hangover cure.
WO2009/027690 discloses peptides that bind α-synuclein and mentions their use in the diagnosis and monitoring of synucleinopathic diseases. WO03/69332 and WO99/50300 discloses method of detecting α-synuclein oligomerisation using monoclonal antibodies.
This invention aims to provide further compounds that can be used in the imaging and/or diagnosing of synucleinopathies in subjects.